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Biomedical subjects

T D Brown

Publications and source records attributed to T D Brown.

At least 109 records · Page 6Linked to original sources
PubMed1995

Articulated external fixation of pilon fractures: the effects on ankle joint kinematics.

The effect of the Orthofix articulated ankle external fixator on ankle and subtalar joint kinematics and fracture fragment motion was investigated in fresh cadaver specimens using biplanar radiographic analysis. The kinematic testing was performed for the normal ankle (i.e., no fixation) and for three alternate fixator hinge orientations. The fixator applications simulated a horizontal ankle axis (the current clinically preferred orientation), an axis coincident with a previously defined approximate ankle axis, and an axis located using a mechanical axis finder. The horizontal fixator application significantly disturbed normal ankle kinematics. Aligning the fixator hinge with an approximate ankle axis caused significant distortion of motion about only two of six possible rotational axes. Aligning the fixator hinge with the (specimen-specific) ankle axis determined by the axis finder most closely matched the motion of the normal ankle. For pilon fractures simulated by a transverse osteotomy, there appeared to be no physiologically significant fracture fragment motions, regardless of fracture stability or fixator orientation.

Ankle Injuries↗
PubMed1995

Theiler's murine encephalomyelitis virus 3D RNA polymerase: its expression in the CNS and the specific immune response generated in persistently infected mice.

Intracerebral inoculation of the neurotropic murine picornavirus, Theiler's murine encephalomyelitis virus (TMEV), results either in an acute encephalitis (GDVII strain) or in the establishment of a persistent infection with the development of demyelinating lesions (BeAn strain). In this article, the expression of the viral RNA polymerase was studied in the central nervous system of both acutely and persistently infected mice and in infected cells in tissue culture. Similar numbers of acutely infected glial cells (80-85%) expressed both viral polymerase and structural proteins in vitro while a much smaller proportion of persistently infected glial cells (0.6-0.9%) expressed these proteins. Following infection of mice with GDVII, many cells in the brain were found to express polymerase. However, in the spinal cord of mice persistently infected with BeAn, very few cells were found to express the polymerase while many more cells showed the presence of viral structural proteins. This suggests that a restriction in viral replication, possibly at the level of polymerase expression, may be a feature of the persistent infection. However, enough polymerase was expressed to maintain a polymerase-specific antibody response in a number of infected animals as late as 21 months post-infection. Mechanisms that may be involved in the establishment and maintenance of TMEV persistence are discussed with reference to these findings.

Animals↗
PubMed1995

A region of the coronavirus infectious bronchitis virus 1a polyprotein encoding the 3C-like protease domain is subject to rapid turnover when expressed in rabbit reticulocyte lysate.

In order to investigate the mechanisms involved in the processing of infectious bronchitis virus polyproteins, several candidate regions of the genome have been cloned and expressed in vitro. During these studies it was observed that the translation product encoded by one of these clones (pKT205) was poorly expressed. Biochemical and genetic analyses revealed that the basis for the poor expression was a post-translational event involving ubiquitination of the protein and degradation by an ATP-dependent system operating in the reticulocyte lysate used for the in vitro expression. Two independently acting regions which conferred instability were identified, one of which mapped to the predicted 3C protease domain, contained within the 5' end of the clone, while the other, more C-terminal region, was effective in conferring instability upon a heterologous protein to which it had been transferred. These regions may influence the stability of the authentic viral protein(s) in vivo and hence allow for the control of their expression and/or function at the level of proteolysis by cellular protease(s).

3C Viral Proteases↗
PubMed1995

Fracture of the acetabulum during insertion of an oversized hemispherical component.

A hemispherical metal-backed acetabular component that was oversized by two or four millimeters was introduced without cement into thirty fresh or embalmed cadaveric acetabula that were fifty, fifty-two, fifty-four, fifty-six, or fifty-eight millimeters in diameter. Manual tapping was used to insert the component into ten fresh and ten embalmed specimens, and a materials testing machine was used for the remaining five fresh and five embalmed specimens. The magnitude of force and the number of pulses necessary to seat the component were determined for the insertions performed with the materials testing machine; 2000 and 3000 newtons of force were required to insert the cups that were oversized by two and four millimeters, respectively. Visual and radiographic assessments were used to identify any resulting acetabular fractures. Over-all, eighteen (60 per cent) of the thirty acetabular specimens fractured. Of the eighteen fractures, only fifteen were detectable radiographically: ten on en face or lateral radiographs of the cup and five only on oblique radiographs of the cup. The remaining three fractures were apparent only after the removal of the acetabular component.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetabulum↗
PubMed1995

An articulated ankle external fixation system that can be aligned with the ankle axis.

Aligning an articulated ankle external fixator with the ankle axis located using a mechanical axis finder has been shown to preserve normal ankle joint kinematics while the fixed hinge device is attached. However, several problems exist preventing the clinical application of this finding for fractures of the tibial plafond. We initiated a series of studies to resolve these issues. First, the accuracy of the mechanical axis finder in biological systems was quantified by comparing it to that of a computationally derived helical axis. Second, a prototype fixator design was developed in the biomechanics lab to increase the versatility of intraoperative fixator placement. Finally, a radiographic method of locating the ankle axis was developed which is based on talar morphology independent of the fractured tibia. The prototype fixator has been accurately aligned along the ankle axis in cadaveric specimens using this method. Open reduction and internal fixation (ORIF) is the accepted method of treatment for tibial plafond fractures. It holds the advantage of sufficient fracture fixation to permit early joint motion. Good results have been reported using this method, but some authors have reported complication rates up to 50%. The wide surgical approaches required, in conjunction with preexisting soft tissue injury, are thought to significantly increase the risk of soft tissue complications. In response to these problems, many investigators are beginning to utilize external fixation as an alternate treatment modality. One external fixation system which has shown particularly good results is a monolateral cross-ankle articulated fixator (Orthofix SRL., Verona, Italy) which allows motion at the ankle joint as the plafond fracture is healing (Figure 1).(ABSTRACT TRUNCATED AT 250 WORDS)

Ankle Joint↗
PubMed1995

Concerns and improvements with cementless metal-backed acetabular components.

The relatively high incidence of acetabular component failure shown in long-term followup studies of cemented total hip replacement has led to the use of noncemented fixation on the acetabular side of the total hip arthroplasty. In the first generation of noncemented acetabular devices, large-size femoral heads requiring thinner polyethylene were used with many of the popular designs. These components were also modular, but the design considerations involved in minimizing polyethylene debris were not fully appreciated. The newer designs of noncemented acetabular components are addressing the need to minimize wear and the production of particulate debris at the bearing surface and metal-polyethylene interface. Newer techniques also have been developed to provide initial component stability and bone-prosthesis contact. With these improvements, the results of noncemented acetabular fixation may outperform the results with cemented fixation. This may be especially true when considering the ease of insertion and versatility of noncemented acetabular components.

Acetabulum↗
PubMed1995

Deoxyspergualin: phase I clinical, immunologic and pharmacokinetic study.

Deoxyspergualin (DSG) is an analog of the polyamine spergualin with preclinical evidence of activity in murine and human tumor models. This phase I study examined a 120 h continuous infusion schedule in 56 patients with refractory solid tumors at doses ranging from 80 to 2792 mg/m2/day. Dose-limiting toxicity was reversible hypotension and appeared to be associated with plasma levels of DSG > 4 micrograms/ml. Other dose-dependent effects noted were pruritus and circumoral paresthesias. Myelosuppression and gastrointestinal toxicities were mild and sporadic. Two patients with refractory head and neck cancer had minor responses. The recommended phase II dose on this schedule is 1800 mg/m2. Additional monitoring to identify immunologic properties included immunophenotyping of peripheral lymphocytes and cytotoxic activity by means of standard 51Cr-release assays. These studies revealed a non-dose-dependent increase in the number of cells expressing T cell antigens predominantly the T suppressor (CD8) phenotype posttreatment. In three patients, a mild increase in LAK activity was noted post-treatment without a consistent relationship to dose or change in cell surface antigens. Pharmacokinetic studies were completed on 26 patients ranging from doses of 80 to 2792 mg/m2. The average plasma concentration ranged from 0.07 to 7 micrograms/ml. DSG was rapidly cleared from the plasma with a mean terminal half-life of 1.9 h. Mean total body clearance was 25.24 l/h/m2. Further in vivo immunologic studies should be pursued while the agent is studied in fixed dosage phase II clinical trials.

Adult↗
PubMed1994

Starting window, a distinct element in the cap-independent internal initiation of translation on picornaviral RNA.

Initiation of translation on picornaviral RNA templates occurs via cap-independent ribosome binding to a cis-acting element, internal ribosome entry site (IRES). Mapping of the starting point of translation relative to the IRES was attempted using Theiler's murine encephalomyelitis virus (TMEV) RNA as a model. The possibility that the starting point is determined by the conserved oligopyrimidine upstream of the initiator codon was studied. In contrast to poliovirus, neither the conserved oligopyrimidine nor an AUG at a fixed distance downstream of this oligopyrimidine are required for efficient translation of the TMEV RNA in Krebs-2 extracts or reticulocyte lysates or for viral infectivity; mutants lacking the oligopyrimidine/AUG tandem were stable upon passage in BHK-21 cells. A short template segment, the starting window, was defined, wherefrom ribosomes begin translation or downstream scanning depending, respectively, on the presence or absence of a good-context AUG within this window. Using a collection of the engineered TMEV mutant RNAs, the starting window was mapped to 16-17 nt downstream of the IRES and was found to be approximately a dozen nt long. The efficiency of translation initiation from an AUG linearly increased upon the 5'-->3' displacement of the initiator codon within the window. The competence of the starting window did not appear to depend markedly on its primary structure; however, it was completely inactivated ("closed") with concomitant dramatic inhibition of total protein synthesis upon conversion of the corresponding RNA segment into a double-stranded form.

Base Sequence↗
PubMed1994

Characterization of a replicating and packaged defective RNA of avian coronavirus infectious bronchitis virus.

The Beaudette strain of IBV was passaged 16 times in chick kidney cells. Total cellular RNA was analyzed by Northern hybridization and was probed with 32P-labeled cDNA probes corresponding to the first 2 kb of the 5' end of the genome, but excluding the leader, and to the last 1.8 kb of the 3' end of the genome. A new, defective IBV RNA species (CD-91) was detected at passage 6. The defective RNA, present in total cell extract RNA and in oligo-(dT)30-selected RNA from passage 15, was amplified by the reverse transcription-polymerase chain reaction (RT-PCR) to give four fragments. The oligonucleotides used were selected such that CD-91 RNA, but not the genomic RNA, would be amplified. Cloning and sequencing of the PCR products showed that CD-91 comprises 9.1 kb and has three regions of the genome. It contains 1133 nucleotides from the 5' end of the genome, 6322 from gene 1b corresponding to position 12,423 to 18,744 in the IBV genome, and 1626 from the 3' end of the genome. At position 749 one nucleotide, an adenine residue, was absent from CD-91 RNA. By Northern hybridization CD-91 RNA was detected in virions in higher amounts than the subgenomic mRNAs.

Base Sequence↗
PubMed1994

Pharmacokinetic and biotransformation studies of ormaplatin in conjunction with a phase I clinical trial.

Ormaplatin is a second-generation platinum (Pt) analogue with in vitro activity against some cisplatin-resistant malignant cell lines. We have evaluated the pharmacokinetics and biotransformations of ormaplatin during a phase I trial in which ormaplatin was administered by daily 30-min infusions on 5 consecutive days every 28 days. Sixteen patients received 25 courses at doses ranging from 5.0 to 11.6 mg/m2 per day. Pharmacokinetic parameters determined for ultrafilterable Pt measured by atomic absorption spectrophotometry revealed a short half-life (t1/2 16 min), moderate volume of distribution (Vd 12 l/m2), and relatively fast systemic clearance (Cls 544 ml/min per m2). Cls and percentage of drug unbound decreased during the 5-day administration period. Average systemic exposure increased with dose; however, inter-individual variability in Cls produced overlap in systemic exposure between the dose levels. The major active biotransformation product [PtCl2(dach)] was evaluated at the highest dose level by HPLC. This product decayed monoexponentially with a mean t1/2 of 13 min and a higher degree of pharmacokinetic variability than that of ultrafilterable Pt at this dose. No unreacted ormaplatin was detected; however, several inactive biotransformation products persisted for at least 120 min. Approximately 32% of the dose was excreted in the urine during the first day, one-third of this during the initial 1.5 h. The human pharmacokinetic characteristics of ormaplatin resemble those of cisplatin; however, additional study will be required to discern which analyte of ormaplatin correlates best with clinical effects.

Adult↗
PubMed1994

Phase II trial of gemcitabine (2,2'-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas.

Gemcitabine is a novel nucleoside analog which demonstrated a broad spectrum of preclinical activity in solid tumor models, and responses in patients with pancreas cancer during phase I evaluation. Patients with measurable adenocarcinoma of the pancreas who had received no previous chemotherapy were eligible for this multicenter phase II clinical trial. Gemcitabine 800 mg/m2 was administered intravenously weekly for 3 consecutive weeks, followed by one week rest, every 4 weeks. Forty-four patients entered the trial; 35 had at least 2 cycles of therapy. Partial response was observed in 5 patients (11%, estimated 95% confidence interval 2-20%), with a median duration of 13 months. All responding patients had stabilization or improvement in performance status. Fourteen patients had stable disease of 4 or more months. The median WBC nadir was 3.8 x 10(3)/microliters (range 1.6-9.3) and the median absolute neutrophil (ANC) nadir was 2.0 x 10(3)/microliters (range 0.4-7.2). Thrombocytopenia - 100.0 x 10(3)/microliters was observed in 15 patients; the median platelet nadir was 123.0 (range 30.0-245.0). All patients experienced a mild to moderate flu-like syndrome. In addition, one patient had a mild hemolytic-uremic syndrome which appeared related to gemcitabine therapy. Gemicitabine demonstrated marginal activity in this resistant neoplasm, without excessive toxicity. Further evaluation, including the use of more intense dosing and/or combination therapy, is warranted.

Adenocarcinoma↗
PubMed1994

Protection against turkey rhinotracheitis pneumovirus (TRTV) induced by a fowlpox virus recombinant expressing the TRTV fusion glycoprotein (F).

A recombinant fowlpox virus was produced which expressed the fusion protein (F) of turkey rhinotracheitis virus (TRTV), a pneumovirus. Turkey poults were vaccinated twice, at an interval of 2 weeks, intramuscularly and by wing web on each occasion, with the recombinant or a control fowlpox virus. Two weeks after the second vaccination the poults were challenged superconjunctivally and intranasally with virulent TRTV. A partially protective immune response was achieved; turkeys vaccinated with the F recombinant showed milder clinical signs and 1000-fold less challenge virus was recovered from the nose and trachea compared with turkeys that had been vaccinated with control fowlpox virus. Expression of the F protein induced antibodies which were detectable both by an ELISA and a virus neutralization test. These results show that the immune responses to the F protein play a major role in protection against TRTV and indicate that recombinant viruses expressing the TRTV F protein have potential as vaccines against TRT.

Animals↗
PubMed1994

Acute effects of smoking on digital artery blood flow in humans.

Smoking induces several immediate physiologic changes in the distal arteries of the human upper extremity. We examined the hemodynamic effects of cigarette smoking on blood flow in normal human digital arteries using 20 MHz pulsed ultrasonic Doppler velocimeter methods. In each of nine subjects, two presmoke measurements and six postsmoke measurements were collected over a 30-minute period. Maximum velocity and volumetric flow data were averaged. Although no statistical differences were present between presmoke and postsmoke variables, maximum velocity decreased 14% and volumetric flow decreased 60% in the first postsmoke measurement interval. These observations suggest that smoking produces increased vascular resistance in the fingers and an overall reduction in both volumetric blood flow through arteries and tissue perfusion.

Adult↗
PubMed1994

Phase I trial of sulofenur (LY186641) given orally on a daily x 21 schedule.

Sulofenur (LY186641), a diarylsulfonylurea, was evaluated clinically utilizing either a daily x 21 schedule or a daily x 5 (with 2 days off) for 3 weeks schedule. Eighteen patients with refractory solid tumors received 47 evaluable courses of sulofenur given p.o. daily x 21 every 28 days at five dose levels while 14 received 29 courses of sulofenur given daily x 5 for 3 weeks every 28 days at three dose levels. Toxicities included anemia, methemoglobinemia and hemolysis. One patient experienced a fatal subendocardial infarction on the daily x 21 schedule. One partial response was observed in a patient with a sertoli cell tumor on the daily x 5 for 3 weeks schedule. Daily x 5 for 3 weeks is the schedule recommended for phase II trials.

Administration, Oral↗
PubMed1994

The complete sequence of a human astrovirus.

We have determined the complete genomic sequence of human astrovirus serotype 1 isolated in Newcastle upon Tyne. The genome is 6813 nucleotides long and contains three sequential open reading frames (ORFs). The two closest to the 5' end are linked by a ribosomal frameshifting motif and contain sequence motifs indicative of non-structural virus proteins: serine protease and RNA-dependent RNA polymerase. A nuclear addressing sequence is also located here. The 3' ORF encodes the virion structural polypeptides as a polyprotein precursor. This genomic organization resembles that of the plant virus family Luteoviridae.

Amino Acid Sequence↗
PubMed1994

The human astrovirus RNA-dependent RNA polymerase coding region is expressed by ribosomal frameshifting.

The genomic RNA of human astrovirus serotype 1 (HAst-1) contains three open reading frames (ORFs), 1a, 1b, and 2. ORF 1b is located downstream of, and overlaps, 1a, and it has been suggested on the basis of sequence analysis that expression of ORF 1b is mediated through -1 ribosomal frameshifting. To examine this possibility, a cDNA fragment containing the 1a-1b overlap region was cloned within a reporter gene and placed under the control of the bacteriophage SP6 promoter in a recombinant plasmid. Synthetic transcripts derived from this plasmid, when translated in the rabbit reticulocyte lysate cell-free system, specified the synthesis of polypeptides whose size and antibody reactivity were consistent with an efficient -1 ribosomal frameshift event at the overlap region. The HAst-1 frameshift signal has two essential components, a heptanucleotide slippery sequence, A6C, and a stem-loop structure in the RNA. The presence of this structure was confirmed by complementary and compensatory mutation analysis and by direct structure probing with single- and double-stranded RNA-specific reagents. The HAst-1 frameshift signal, like that present at the overlap of the gag and pro genes of the retrovirus human T-cell lymphotrophic virus type II, does not involve the formation of an RNA pseudoknot.

Animals↗